new treatments for lupus by daniel j. wallace, md
DESCRIPTION
A presentation by Daniel J. Wallace, MD from Lupus LA's 4th Annual Patient Education Conference at Cedars-Sinai in Los Angeles, CA.TRANSCRIPT
1
NEW THERAPIES FOR SLE
DANIEL J WALLACE MD
Clinical Professor of Medicine
Cedars-Sinai Medical Center
David Geffen School of Medicine at UCLA
2
2005 FDA Guidance Document for SLE• The drug is safe
• Clinical indices must be improved (BILAG+ either SLEDAI, SLAM or ECLAM)
• Clinical response index (e.g., RIFLE)
• Quality of life improvement
• ACR/SLICC Damage Index
• Organ specific measures
• Subpart H: surrogate markers or biomarkers
3
SLEDAI (Systemic lupus disease activity index)• Evaluates 24 components and emphasizes organ activity
as opposed to laboratory abnormalities
• 105 possible points---64 of which are central nervous system and 16 are renal
• Anti DNA, C3, Leukopenia, Thrombocytopenia are the only blood determinations and if all abnormal account for only 6 points
• Does not include: hemolytic anemia, pulmonary hypertension, TTP, mesenteric vasculitis, pulmonary hemorrhage
• SLEDAI Flare Index requires a change of 4 points
4
BILAG (British Isles Lupus Assessment Group)
• 8 organ systems with 86 items weighted as 0-4 (not present to new or improved)
• Organ systems: constitutional, musculoskeletal, renal, nervous system, hematologic, cutaneous, cardiopulmonary, eye, gastrointestinal
• Rated A-E (life threatening to not present)
• BLIPS software
• End points as new BILAG A or B
5
Clinical validation of the CLASI• An ACR and dermatology group derived the CLASI (Cutaneous Lupus
Erythematosus Disease Area and Severity Index) (J Inv Derm 2005; 125:889-94) for use in assessing skin scores in clinical trials (analagous to the PASI for psoriasis) fulfills the FDA guidance document’s requirements for validated organ specific measures in following lupus patients
• Index contains weighted anatomic locations, activity (erythema, scale/hypertrophy), damage (dyspigmentation, scarring, atrophy, panniculitis), mucous membranes and alopecia
• First attempt to validate it (abst #1010) in a pilot study of 9 patients at U of Penn given drug interventions was promising but needs much greater experience
6
Newer agents for SLE• Mycophenolate mofetil
• Topical pinecrolimus and tacrolimus
• Tacrolimus
• Leflunomide
• Infliximab and other TNFi
7
Lupus Nephritis• Cost
– Direct medical costs are 4x higher for lupus nephritis pts compared with SLE pts without nephritis ($19,250–$42,174/yr vs $4700–$10,015/yr)
– Extra costs due to hospitalizations and/or dialysis• Response to standard therapy
– 80% respond to IV cyclophosphamide– 35% relapse rate– 10% dialysis
• Poor prognostic factors– AA race does not respond as well to IV cyclophosphamide– Poor initial response– Renal relapse
Houssiau F, 71st ACR, Boston 2007, ACR Clinical Symposium; Clarke A. ibid, #503; Li T, et al. ibid, #1255;Ginzler E, #L13
• Efficacy and safety study to demonstrate superiority of MMF over IVCy in Lupus nephritis (WHO III, IV)
• Induction protocol (370 pts randomized to one of two therapies for 24 wks)• MMF 3 g/d (185 pts)• IV cyclophosphamide 0.5–1.0 g/m2 monthly (185 pts)• All pts received prednisone 60 mg/d with taper
• Response: stable/improved Cr and improved proteinuria
Aspreva lupus management study (ALMS)
8
ALMS: Efficacy and Safety Results
• Conclusions– MMF equal to IVCy for induction– AA and Hispanics may respond better to MMF than
to IVCy– Safety
• MMF: 24 AEs; 12 infections; 9 deaths (7 from infection)• IVCy: 13 AEs; 4 infections; 5 deaths (2 from infection)
Total (%)Caucasian/Asian (%)
AA (%)Hispanic
(%)
MMF 56 56/53 60.4 60.9
IVCy53
(p=NS)
54/64
(p=NS)
38.5
(p=0.033)
38.8
(p=0.011)
Ginzler E, et al. 71st ACR, Boston 2007, #L13
9
Targets for New Therapies in SLET cells CTLA4 Ig; modified CD40L mAb
B cells, anti-dsDNA antibodies LJP 394; mAbs to CD20, CD22
antiBLyS, TACI-Ig, BAFF-RFc
Complement anti C5a (approved for PNH)
Cytokines mAbs to IL-10, sIL-6R, IL-6
Promote regulatory cells Expand CD4+CD25+ cells, CD8+CD28- cells
Inhibition of interferon, toll receptors
Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9
T cell regulation of autoantibody production
Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide)
10
How are T-cells activated?• CD80/86:CD28 is one of the best characterized co-stimulatory
pathways– Signal 2
CD80/86:CD28 facilitates T-cell activation, proliferation, survival
and cytokine production
CD28 constitutively expressed on T-cell surface; CD80/86 on APC binds
CD28 on T-cell = signal 2C
D28
ActivatedT-cell
Site of action of abatacept
Antigen
11
Survival of Lupus Mice Treated withCTLA4Ig and Anti-CD40L
Wang et al. J Immunol. 2002;168:2046–2053.
Control
CTLA4Ig/anti-CD40L
CTLA4Ig
Anti-CD40L
Weeks
% A
live
28 38 48 58 68 78 88
100
80
60
40
20
0
12
Phase 2 Trial of Abatacept• Randomized, double-blind, placebo-controlled, phase 2
study• Abatacept compared with Placebo on a background of
oral glucocorticosteroids for subjects with SLE and the prevention of subsequent lupus flares
• Primary objective of this study will be to assess the proportion of subjects with new clinical flare of SLE (BILAG "A" or "B") during the 1 year double-blind treatment period
• Secondary objective of this study will be to assess proportion of subjects with a new clinical flare of SLE (BILAG A or B) within the initial 6 months of the double-blind treatment period and evaluate the proportion of subjects who during the study experienced a BILAG A or B flare
• Expected Total Enrollment is 180
Source: www.clinicaltrials.gov. Accessed January 29, 2007.
13
T-lymphocyte co-stimulatory modulation: Importance of the T-cell subsets
Adapted from Janeway CA Jr, et al. Immunobiology: The Immune System in Health and Disease. 6th e. New York, NY: Garland Science Publishing: 1994. p347
CTLA-Ig Less dependent CTLA-Ig More dependent
Anti-viral / anti-tumor immunity
CD8 T-cells:Peptide + class I
CD4 T-cells:Peptide + class II
Inflammation / Ab production
T T
Dougados M, et al. EULAR 2007, Barcelona, #SP0068
14Dougados M, et al. EULAR 2007, Barcelona, #SP0068
T-lymphocyte costimulatory modulation consequences
• Activation of the co-stimulation– Anti-tumoral effect?– Autoimmune disorders
• Inhibition of the costimulation?– Pro-tumoral effect?– Prevention of autoimmune disorders?
15* in Rilex, June 2005; * in Dillon 2006
Co-stimulation modulator Human diseases
Inhibition
CTLA-4 Ig (abatacept) RA (registration) SLE Juvenile Chronic Arthritis, Multiple sclerosis
LEA29Y (belatacept) Organ transplantation
Anti-CD80/86 Organ transplantation
Anti-CD80 Psoriasis SLE
Anti-BAFF (belimumab) RA SLE
TACI-Ig RA, Lymphoma SLE, Multiple sclerosis
Anti-BAF (AM6, G3) RA SLE
BR3-Fc RA
Anti-α 2 integrine (natalizumab) Multiple sclerosis Crohn's disease
Activation
Anti-CLA-4 (Ipilimumab, ticilimumab)
Tumors
Anti-CD28 (TGN1412) Leukemia Renal cancer
CC-5012 (CD28 activator) Myeloma
CD28 agonist Tumors
Selective co-stimulation modulators in clinical development **
Dougados M, et al. EULAR 2007, Barcelona, #SP0068
16Ng KP, et al. EULAR 2007, Barcelona, #OP0020
Targeted therapeutics: Approaches in SLE
APC T B YCTLA4-Ig CD22
B-cell toleragen
BlySSTACI-IG
CD20
IL-10
Peptide
Antibody
IL-10Apoptoticmaterial
1
2
Cos
timul
ator
y
Fact
ors,
eg
, Bly
S
17
Antigen Independent PhaseAntigen Independent Phase Antigen Dependent PhaseAntigen Dependent Phase
Targets for BLyS/BAFF inhibitors
Targets for Rituximab, Ocrelizumab, Ofatumumab
CD45CD45(AKA (AKA B220)B220)surface surface markermarker
Activated Activated B-cellB-cell
PlasmaPlasmacellcell
SecretedSecretedIgG, IgA, IgG, IgA,
IgE, or IgMIgE, or IgM
Mature Mature B-cellB-cell
Pro-B-cellPro-B-cell Pre-B-cellPre-B-cell Immature Immature B-cellB-cell
Surrogate Surrogate light chainlight chain
DDHHJJHH
IgMIgM IgMIgM IIggDD
AntigenAntigen
IgM, IgD, IgM, IgD, IgA, or IgEIgA, or IgE
CD40L andCD40L andcytokinescytokines
CD40CD40
VVHHDDHHJJHH VVLL JJLL
Adapted from Sell S, et al. Immunology, Immunopathology, and Immunity. 6th ed. Washington, DC: ASM Press; 2001
Potential targets in B-cell lineage
18
Uncontrolled Data of Rituximab in SLE and SS• Two placebo-controlled trials underway in SLE (SS?) (EXPLORER
and LUNAR)• 9 uncontrolled studies presented in lupus and Sjogren’s• New insights from in uncontrolled studies include:
– NK cell levels surge just as B-cell recovery begins– Persistence of B-cells predicts a poorer outcome– Drug may be more effective when used with CTX– In membranous nephritis, rebiopsy shows resorption of immune
depositions– 20% with SLE develop with HACA (3x that reported with RA)– Responses can last up to 1 y. 1/3 don’t require further immune
suppressive Rx– 16 patients with primary Sjogren’s: salivary gland B-cell
morphology returned to baseline after 18 months (ISRs and serum sickness reported in some pts)
– Drug is safe in children with lupus
Ng KP, et al. ACR, Washington DC 2006, #536; Tanaka Y, et al. ibid, #537; Gunnarsson I, et al. ibid, #538; Jónsdóttir T, et al. ibid, #539; Luning Prak ET, et al. ibid, #540; Dass S, et al. ibid, #541; Pers JO, et al. ibid, #1770; Gunnarsson I, et al. ibid, #2097
19Anolik JH, et al. EULAR 2007, Barcelona, #SP0033
B-cell depletion is variable
0.1
1
10
100
0 3 6 9 12
Months
CD
19+
(ly
mp
ho
cyte
s/u
L)
Non-depleters (n=6)
Depleters (n=11)
Recovery to 60% of baseline at 12 monthsFull recovery at 2–3 years in all but 1
201. Genovese M, et al. EULAR 2007, Barcelona, #SAT0008; 2. Manning W, et al. ibid, #SAT0018
Ocrelizumab: Humanized anti-CD20 mAb is effective in RA – 24 Week Phase 1/21
• 237 patients: All RF+; IR to MTX:– Ocrelizumab 10, 50, 200, 500,
1000 mg IV Day 1 and 15 or Pbo
• Dose dependent B-cell depletion and increases in serum BAFF ²
• Most frequent AEs: infusion-associated HA, nausea, chills, pyrexia, dizziness– SAEs and SIEs similar between
active and placebo
• HAHAs Wk 24: 10mg: 19%; 50mg: 10%; 200mg: 0; 500mg: 0; 1000mg: 2.5%
• Conclusions: – No apparent dose response– progressing to phase 2/3
0
20
40
60
80
PlaceboN=41
10mgN=36
50mgN=40
200mgN=40
500mgN=40
1000mgN=40
% r
es
po
nd
ers
ACR20 ACR50 ACR70
0
20
40
60
80
PlaceboN=41
10mgN=36
50mgN=40
200mgN=40
500mgN=40
1000mgN=40
% r
es
po
nd
ers
EULAR Mod/Good DAS Remission
ACR response
EULAR response
21
Synthetic anti-CD 20 – TRU-015: Ongoing Phase II RCT• CD20-directed SMIP (single-
chain polypeptides), smaller than antibodies
• Mediates ADCC and CDC
• 36 patients w/ active disease despite MTX
• 5 mg/kg IV x1 or 2.5 or 7.5 mg/kg
IV q week x2
• Study ongoing; interim data
• Generally well tolerated
• No infectious or non-infectious SAEs
• B-cell depletion in all cohorts
• B-cell recovery starts at 16 weeks
0
10
20
30
40
50
60
70
80
90
All RF +
% r
esp
on
se
ACR20 ACR50 ACR70
ACR20 at Week 24
Burge DJ, et al. ACR, Washington DC 2006, #463
22
Mechanism of Anti-CD20 (Rituximab) and Anti-CD22 (Epratuzumab) Monoclonal Antibodies
CD22
CD20
B cell
• Antibody-dependent cell-mediated cytotoxicity
• Complement-dependent cytotoxicity
• Apoptosis
• Modest antibody-dependent cell-mediated cytotoxicity
• No complement-dependentcytotoxicity
• Immunomodulatory and antiproliferativeeffect
Anti-CD20 MAbRituximab
Chimeric IgG1κ
Anti-CD22 MAbEpratuzumab
Humanized IgG1
Carnahan et al. Mol Immunol. 2007;44:1331–1341.
23
B-cell–targeted therapies• Anti-CD20 agents:
– Rapidly deplete peripheral B-cells via ADCC and CDC– First dose infusion reactions due to rapid cell death, cytokine
release– Immunogenicity in part related to cell death/debris– Despite fully human or SMIP -single chain polypeptides, smaller
than antibodies; expect immunogenicity
• B-cell growth factors (BLyS/BAFF/APRIL) antagonists– Slower depletion of B-cells – Peripheral and germinal center B-cells undergo apoptosis due to
absence of growth factors– Onset of benefit generally occurs over 3-6 months– Less severe infusion reactions– Less immunogenicity
24
B-cell growth factors
Ligands
Receptors BAFF-R BCMA TACI
BLyS APRIL Heterotrimer
Proteoglycans
Increased B-cell survivalCostimulation of B-cell prolferation
Ig class switch recombination Enhanced APC function Germinal center formation Regulation of B-cell tolerance
Sequester APRIL at cell surface to improve TACI and/or BCMA signalling?
Mediate plasma cell trafficking
Issacs JD, et al. EULAR 2007, Barcelona #SP0069
25
Belimumab (lymphoStat-B)
• Fully-human monoclonal antibody
• Selectively targets and inhibits soluble BLyS– TNF family member that
promotes B-cell differentiation, proliferation, and survival
– Plays critical role in physiologic B-cell development and induces B cells to secrete immunoglobulins
• Inhibition of BLyS can result in autoreactive B-cell apoptosis
26
Systemic Lupus: Belimumab
• Phase 2: 52-week, randomized, double-blind, placebo-controlled trial.
• n=449…but subset analysis using 71.5% of patients defined by ANA>1:80 or dsDNA >30 IU. Moderately ill SLE: baseline mean SELENA SLEDAI= 9.6.
Ginzler E, et al. EULAR 2007, Barcelona, #OP0018
27p<0.01 for the comparison between all active vs placebo from Day 56 through Day 364
Belimumab reduced CD20+ B cells by 61% at Week 76
Furie R, et al. ACR, Washington DC 2006, #535; Wallace D, et al. ibid, #2012; Stohl W, et al. ibid, #1985
28Ginzler E, et al. EULAR 2007, Barcelona, #OP0018
Novel combined endpoint*
>4 point improvement in SELENA SLEDAI score
AND
No new BILAG 1A/2B flares
AND
No worsening in Physician’s Global Assessment (<0.3 point increase)
* Accepted by Regulatory Authorities for Phase 3 Trials
29Ginzler E, et al. EULAR 2007, Barcelona, #OP0018
Combined response rate for belimumab patients significantly higher
46% combined response rate for serologically active patients on belimumab vs 29% for placebo at Week 52
56% combined response rate for patients on belimumab at Week 76* p=0.0059 at Week 52, p=0.02 at Week 56
0
10
20
3040
50
60
70
0 28 84 140 224 280 336 392 476 532
Visit day
Res
po
nd
er r
ate
in
sero
log
ical
ly a
ctiv
e p
ts (
%)
PlaceboPlacebo to 10 mg/kg
All active
30
Atacicept inhibits the function of BLys and APRIL• Atacicept is a fusion protein formed between the extracellular
domain of the naturally occurring human TACI receptor and the Fc domain of human IgG1
Atacicept
Extracellular domainof TACI receptor
Fc domain of human IgG
rDNA technology
B-cell
31
Systemic Lupus: Atacicept (TACI-Ig)• 2 Phase I studies of PK and biologic activity
• Appears tolerated and safety is favorable
• Good signs of biologic effects on B-cells whether IV or SC
• Interestingly, measured atacicept-BLys complexes in peripheral blood
• Further development and trials are planned
32
Phase I trials for lupus: Tociluzimab• anti-IL-6R mAb
• Phase I: 16 patients, 6 doses over 12 weeks (3 dosing regimens)
• Safety signals
– Significant decrease in absolute neutrophil count in 60% of patients at highest dose
• Significant decreases noted in IgG and ds DNA Abs
• Significant improvement in SLEDAI and SLAM scores
1. Illei G, et al. ACR, Washington DC 2006, #L20; 2. Dall'Era M, et al. ibid, #L19
33
Mechanism of LJP 394 (Abetimus)• Novel synthetic putative
B-cell toleragen– Four double-stranded
oligodeoxyribonucleotides plus non-immunogenic PEG carrier
– Acts as anti-anti DNA to reduce anti-dsDNAantibodies in SLE patients
– Awaiting results of phase III study with an endpoint of time to nephrotic flare
Alarcon-Segovia et al. Arthritis Rheum. 2003;48:442-453.Furie. Rheum Dis Clin North Am. 2006;32:149-156.
B cell
B-cell receptor
B-cell toleragen
34
Cumulative Renal Flare in Phase 3
Cumulative renal flares by week
0
5
10
15
20
25
30
0 16 32 48 64 80
LJP 394 Placebo
Patients
Week 0
16 32 48 64 88
LJP394
145 111 81 67 50 27
Placebo
153 118 98 82 59 32
35
Tolerance Mechanisms: Edratide (TEVA)
Tsubata et al. Autoimmunity. 2005;38:331-337.
B cell
BCR
Bone Marrow Peripheral lymphoid organs
Reactive to self antigens
B cell
BCR
Self antigen
Deletion
T-cell zoneB cell
BCR
Self antigen
Deletion
Anergy
Receptorediting
B cell
BCR
Self antigen
Deletion
B cellBCR
Follicle
36
IFNgIL-10BlySTNFaIL-1
IL-12
Innate Immune Responses in SLE
• Toll-like receptors 7 and 9 in immature DC activated by complexes of self protein + RNA (TLR7) and DNA (TLR9)
• These complexes are normally rapidly cleared, but accumulate in SLE• Clearance defects in mice or humans → SLE • Activation of TLR7/9 induces immature DC secretion of IFN-α
immature DC induce T and B cell responses against the RNA and DNA and associated proteins
Activated B cell
Activated T cell
B cell
T cell
Mature DC
Activated mono/macrophage
Immature DC
INCREASED IFN
BacteriaViruses
SLE DNA/IC
CpG DNAssRNAdsRNA
Immune complexes in
SLE bind TLR7 and 9
37
Induction of type I Interferon pathway through Toll-like receptors
TLR3 TLR4 TLR7/8 TLR9
Inflammatory CytokinesType I Interferon
Inflammatory Cytokines Inflammatory CytokinesType I Interferon
PotentialEndogenousLigands:
dsRNA
∞RNA-containingImmune Complexes
FibronectinProducts
CpG DNA-containingImmune Complexes
ExogenousLigands: LPS ssRNA Demethylated
CpG DNA
dsRNA-containingImmune Complexes
TRAM TIRAPTrf
Trf MyD88
MyD88 MyD88
38
Toll-like Receptors in RA and SLE
• In RA – increased TLRs 3, 4, 7 on
dendritic cells (DC)1
– increased viral ds-RNA in joints compared with OA2
• In mouse models arthritis– TLR 2 deficiency decreased
susceptibility to arthritis,– TLR4 deficiency decreased
severity, erosions – Abs to TLR 4 prevented
arthritis1
• DS-RNA arthritogenic when injected into mouse joint, mediated by type 1 IFN from DC2
• CpG DNA sequences, common in bacterial DNA bind TLR 7 and 9 in DCs and B cells.
• Lupus immune complexes bind TLR 7 and Fcγ on DC, releasing cytokine and IFN3
• Antimalarials block the activation TLR 7 and 9
• IFN increase SLE flares and increased in SLE serum
• IFN signaling molecule Stat1 upregulated in SLE4
Genentech, Coley and MEDI-545 clinical trials
1. Radstake TR, et al. EULAR 2007, Barcelona, #SP0136; 2. Magnusson M, et al. ibid, #SP0112; 3. Richez C, et al. EULAR 2007, Barcelona #OP0179; 4. Karonitsch TM, et al. ibid, #OP0178; 5. Means TK, et al. J Clin Infect 2005;115:407
RA SLE
39
Hydroxychloroquine, “Antimalarials” are TLR Antagonists
1. Hydroxychloroquine and other “antimalarials” have been used in treating SLE and RA for decades, but MOA was unknown
2. Recent discovery: these antimalarials are TLR7/8/9 antagonists at clinically relevant doses
3. New approach to treatment – develop improved TLR antagonistsa. Small moleculeb. Orally available
40
CPG 52364 showed dose-dependent inhibition of TLR9-mediated IP-10 induction in mice
Female adult BALB/c mice (n=5/gp) received different doses of CPG 52364 or chloroquine by IP injection. At 1 h post dose, animals received 100µg CpG-DNA ODN subcutaneously. Plasma was collected at 3 h post agonist injection and used for IP-10 assay by ELISA. Value are presented as percent mean TLR9 agonist activity.
Female adult BALB/c mice (n=5/gp) received different doses of CPG 52364 or chloroquine by IP injection. At 1 h post dose, animals received 100µg CpG-DNA ODN subcutaneously. Plasma was collected at 3 h post agonist injection and used for IP-10 assay by ELISA. Value are presented as percent mean TLR9 agonist activity.
41
Hydroxychloroquine (HCQ) and Toll Receptors• TLRs 7, 8 and 9 are activated
inappropriately by endogenous RNA and DNA in SLE. This is inhibited by HCQ, which was thought to work primarily by diminishing antigen presentation
• Mice were treated with HCQ for 5 days. TLR9 activation was strongly inhibited (and to a lesser extent TLR 7). Ag presentation was incompletely blocked.
• The TLR mechanism is more important than antigen presentation inhibition and TLR antagonists represent a novel approach for SLE therapeutics
Weeratna R, et al. 71st ACR, Boston 2007. #1310
42
SLE is a Disease of TLR-Driven Amplification of Autoimmunity
Dendritic CellsTLR7+ / 8+ / 9+
B cellsTLR9+ / TLR7
Inducible
Cytokine/Chemokine InducedActivation/Maturation
And Damage
Apoptotic debrisSelf-antigen
Autoimmune Complex-DrivenTLR Cellular Activation
TLR signal
Anti-self responseCytokine/chemokine
TissueDamage
End OrganFailure
T-cell NK cell
Inflammation
CPG 52364TLR7/8/9 Antagonist
XX
Complexuptake
XX
CPG 52364 (Coley) is a TLR 7,8,9 antagonist in a Phase I trial with similar actions to hydroxychloroquine
Akira S, et al. Nat Imunol 2001;2:675; Lipford G, et al. 71st ACR, Boston 2007. #1596
43
Interferons and Systemic Lupus Erythematosus
• Type I interferons (IFNs) may play a critical role in the pathogenesis of systemic lupus erythematosus (SLE) – Serum IFN-α levels are elevated in patients with SLE1
– Increased expression of type I IFN-induced genes in blood and involved tissues in SLE2
– Correlation between IFN levels and expression of type I IFN-induced genes and SLE activity1,3
– Development of SLE in patients undergoing IFN-α treatment4
– Inhibition of IFN-α may provide therapeutic benefit in the treatment of SLE
1 Hooks JJ, et al. New Engl J Med. 1979;301:5-8; 2 Crow M. Arthritis Rheum. 2003;48:2396-2401; 3 Dall’era MC, et al. Ann Rheum Dis. 2005;64:1692-1697; 4 Ioannou Y, Isenberg DA. Arthritis Rheum. 2000;43:1431-1442.
44
MEDI-545 (Medimmune/AstraZeneca)• Fully human anti–IFN-α IgG1k
monoclonal antibody
• Inhibits IFN-a signaling through IFN-α receptor (IFNAR)
• Double-blind, placebo-controlled phase I trial of single escalating dose, intravenous MEDI-545 (0.3–30 mg/kg) in patients ≥18 years old with SLE – 2:1 randomization, 84-day
follow-up
• There was no safety signal observed
• Effects of MEDI-545 on neutralization of type I IFN gene signature in blood and skin and on disease activity were explored
Wallace D, et al. 71st ACR, Boston 2007. #1315
IFN-a
IFNAR1IFNAR2
PPSTAT2PP
IRF-9
STAT2PP
STAT1PP IRF-9
Tyk2Tyk2Tyk2Tyk2
STAT1
P
Jak1Jak1Jak1Jak1
45
MEDI-545 Reduces Type I IFN Gene Signature, Type I IFN–Induced Proteins in Skin, and Improves Disease Activity
Day 14
Skin, day 0–28
5/1729%
1/333%
MEDI-545Placebo0
20
30
40
Pts
, N
10
>3 point increase in SLEDAI score<3 point increase in SLEDAI score
P=0.0136
Wallace D, et al. 71st ACR, Boston 2007. #1315
Type I IFN–induced proteins in skin
Change in proteinChange in transcript
20%97%
75%99%
87%99%
HERC5 ISG15 IP10
Improvement in disease activity
Day 0
Day 14
46
MEDI-545 Can Normalize Type I IFN Gene Signature in Blood: Heat Map of Gene Expression
Day Neutralization
Wallace D, et al. 71st ACR, Boston 2007. #1315
Calculation based on top 25 type I IFN–inducible genes upregulated in whole blood of one patient treated with 30 mg/kg MEDI-545 (day 0, 1, 4, 7, 14)
47
Th1/Th2 Paradigm
T-bet
Naïve T-cell
IL-5
IL-10
IL-13
IL-4
IL-6
Helminth protection (allergy, atopy, SLE)
IL-4
STAT6
GATA3
CMAT
IL-12
IL-18
Th1 cell
IFN-LT-IL-2IL-22
Cell-mediated immunity
Intracellular pathogens
AutoimmunityIL-12RIL-18R
Th2 cell
Schulze-Koops H, et al. EULAR, 2006, Amsterdam, #SP0130. Zhu J, et al. Cell Res 2006;16:3
(-)
(+)
(-)
(+)
48
FoxP3
T cell subsets: Th17 and Treg cells• Th17 cells are abundant in gut, maintain mucosal homeostasis
• Upregulated in inflammatory diseases including MS, RA, IBD
• IL-23 important for the maintenance of the Th17 phenotype
Treg cell
Self Ag + TGF
IL-10
TGFPROTECTION
IL-17
IL-22
INFLAMMATIONSelf Ag + TGF + IL-6
IL-23 (survival)
IL-23R
CTLA-4
TGF
AITR, GITRNaïve T-cell
RORt
Th17 cell
Betelli, et al. Nature 2006;441:235; Ivanov, et al. Cell 2006;26:1121; Tesmer L, et al. 70th ACR, Washington DC, 2006. #297
49
T-regs in autoimmune disease• CD4+CD25+ regulatory cells prevent the activation of autoreactive T-
cells• T-cells from lupus prone mice are relatively resistant to the
suppressive effect of CD4+CD25+ • Work at the NIH (Lipsky et al) suggests CD4+CD25+ upregulation is a
potential therapeutic avenue in lupus management • Active as opposed to inactive SLE is associated with less
CD4+CD25+ activity (poster and picture represented on the slide
Bonelli M, et al. EULAR 2007, Barcelona #FRI0080
50
Vitamin D and IL-10: An importantpotential link in SLE• IL-10 is a complex cytokine whose levels are
elevated in SLE and has both pro- and anti-inflammatory effects
• Vitamin D levels are decreased in SLE
• Vitamin D independently promotes IL-10 secretion
• Activated B cells produce Vitamin D which down regulates the immune response
• Efforts to produce a Mab to IL-10 are potentially problematic
1. Radbruch, et al. EULAR 2007, Barcelona; 2. Kamen DL, et al. Autoimmune Rev 2006;5: 114–7
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Vitamin D May Play a Role in SLE
• 25-OH vitamin D inhibits Th1 cell proliferation, cytokine production, autoantibody production and APC activation in SLE patients; may be clinically relevant
• 124 Toronto women with SLE who underwent DEXA scanning had significantly lower levels of 25-OH vitamin D levels compared with other DEXA patients; this finding did not correlate with bone density.
• Among 274 Israeli lupus patients, 38% had low vitamin D levels and higher SLEDAI and ECLAM scores. Hydroxychloroquine-treated patients had higher vitamin D levels, corticosteroids had no impact
71%
38%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Insufficient Deficient
Insufficient: <30ng/ml of 25-0H vitamin DDeficiency: <15ng/ml of 25-0H vitamin D
Amital H, et al. 71st ACR, Boston 2007. #535; Toloza S, et al. ibid. #1117; Cantorna et al. Exp Biol Med, 2004
52
IL-18 and SLE• A member of the TNF
superfamily which supports the expansion of Th1 and NK cells
• Mouse models of SLE overexpress IL-18
• Increased levels in SLE sera and renal tissue which correlates with TNF levels and disease activity
• Administration of infliximab decreases expression of IL-18. Targeted therapies against IL-18 are in development
Aringer M, et al. EULAR 2007, Barcelona, #OP0177
TN, IL-18 and SLE activity
Ser
um
TN
F (
pg
/ml)
0
200
100
300
0 4 8 12SIS
t=0.76, p<0.0001
Ser
um
IL-1
8 (p
g/m
l)
0
200
100
300
0 4 8 12SIS
t=0.38, p<0.02
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Microparticles and lupus• 200-700 nm in size surrounded by phospholipid bilayers
• Released by cell death to the surface; taken up by macrophages and induce apoptosis and T cell proliferation
• 40 SLE pts and matched controls— increased levels that correlated with SLEDAI scores
• Also increased in Sjogren’s, vasculitis, antiphospholipid syndrome in other studies
Huber L, et al. EULAR 2007, Barcelona #OP0180
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Targets for New Therapies in SLET cells CTLA4 Ig; modified CD40L mAb
B cells, anti-dsDNA antibodies LJP 394; mAbs to CD20, CD22
antiBLyS, TACI-Ig, BAFF-RFc
Complement anti C5a (approved for PNH)
Cytokines mAbs to IL-10, sIL-6R, IL-6
Promote regulatory cells Expand CD4+CD25+ cells, CD8+CD28- cells
Inhibition of interferon, toll receptors
Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9
T cell regulation of autoantibody production
Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide)
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New therapies for APS• Biologics: LJP 1082
• Oral heparins
• Rituximab
• Glycoprotein IIb/IIIa specific antagonists
• Tissue factor expression inhibitors
• P38 MAPK inhibitors
• Thromboxane A2 inhibitors
• Anti C5a